The purpose of this research study is to determine if selumetinib is safe and effective in treating patients with cancers with a mutated BRAF gene. Selumetinib is an investigational drug that works by blocking a protein called MEK, which is known to play a role in the growth of cancer cells lines and tumors that have a mutated BRAF gene. There are multiple types of cancers that have mutations in the BRAF gene and depend on the activity of this gene for their growth and survival.
Name: Selumetinib
Description: Percentage of participants achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans (which are done every 6 weeks).
Measure: Objective Response Rate in Patients With Cancers Other Than Melanoma Time: 4 yearsDescription: Correlation between response to AZD6244 and mutational analysis of AKT pathway (an intracellular signaling pathway important in regulating the cell cycle)
Measure: AKT Pathway Activity Time: Up to 4 yearsDescription: Percentage of participants with either colon cancer or non-small cell lung cancer achieving either complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of the longest diameter of target lesions, when compared with baseline) using CT (computed tomography) scans.
Measure: Objective Response Rate in Patients With Non-small Cell Lung Cancers and Colon Cancers Time: Up to 4 yearsDescription: Reported as percentage of participants alive and progression free at 4-months. Will be estimated using Kaplan-Meier survival curves. Confidence intervals will be calculated and reported.
Measure: Progression-free Survival Time: 4 monthsAllocation: N/A
Single Group Assignment
There is one SNP
Confidence intervals will be calculated and reported.. Sensitivity and Specificity of Detection of the BRAF V600E Mutation in CTC Using the CTC-chip. --- V600E ---
Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Adult Solid Neoplasm PRIMARY OBJECTIVES: I. To evaluate the objective response rate to AZD6244 (selumetinib) in patients with cancers other than melanoma in which BRAF mutations have been identified prospectively. --- V600E ---
Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Inclusion Criteria: - Ability to understand and willingness to sign a written informed consent document - Histologically confirmed metastatic or unresectable solid tumor - Results from tumor tissue analysis that show a glutamic acid-for-valine substitution at amino acid position 600 in the BRAF gene (V600E) or other activating BRAF mutation, as determined by high-throughput genotyping - Patients may have received any number of prior systemic treatments for their cancer - At least one measurable site of disease by CT, according to standard RECIST criteria 1.0 - ECOG performance status 0-1 - Absolute neutrophil count > 1500 per cubic mm - Platelet count > 100,000 per cubic mm - Hemoglobin > 9 g/dl - Serum bilirubin < 1.5 x upper limit of normal - Serum AST and ALT < 2.5 x upper limit of normal (=< 5 x upper limit of normal, for liver metastases) - Serum creatinine < 1.5 x upper limit of normal - For women of childbearing potential, negative serum pregnancy test and use of physician-approved method of birth control throughout the study Exclusion Criteria: - Estimated life expectancy > 12 weeks - Patients with melanoma - Have received chemotherapy or radiotherapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C), or a targeted therapy within 2 weeks prior to entering the study - Have not recovered from adverse events due to agents previously administered (CTCAE v3 grade 1 or baseline) - Currently receiving other investigational agents - Known brain metastases, unless treated and stable off of corticosteroids for at least four weeks - History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 - Prior treatment with a selective inhibitor of RAF or MEK (e.g., RAF265); (note: prior sorafenib is allowed) - Uncontrolled intercurrent illness, including but not limited to: - Clinically significant active infection - Symptomatic congestive heart failure, unstable angina pectoris, and/or cardiac arrhythmia other than atrial fibrillation - Psychiatric illness/social situations that would limit compliance with study requirements - Refractory nausea or vomiting, swallowing disorder, or malabsorption syndrome that would interfere with swallowing or absorbing the study medication - Pregnant and/or breast-feeding women - Previous or concurrent malignancy, except for the following circumstances: - Disease-free for at least three years and deemed by investigator to be at low risk for recurrence of that malignancy - Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin) - History of solid organ transplantation or other condition requiring the use of immunosuppressive medications - Uncontrolled hypertension (systolic BP >= 150 or diastolic BP >= 100 that cannot be controlled with medications) - A mean left ventricular ejection fraction (LVEF) less than 45% Adult Solid Neoplasm PRIMARY OBJECTIVES: I. To evaluate the objective response rate to AZD6244 (selumetinib) in patients with cancers other than melanoma in which BRAF mutations have been identified prospectively. --- V600E --- --- V600E ---
To estimate the sensitivity and specificity of detection of the BRAF V600E mutation in circulating tumor cells (CTC) using a microfluidic platform (the 'CTC-chip'). --- V600E ---